Novel agents targeting inflammation in SCD. Multiple cell types, molecules, and pathways contribute to the chronic inflammatory state in SCD. In SCD, as in asthma, leukocyte membrane phospholipids are hydrolyzed into arachidonic acid (AA), which is metabolized via the 5-lipoxygenase (5-LPO) pathway, leading to formation of inflammatory leukotrienes. Inhibition of this pathway by several agents currently used in asthma (mometasone, zileuton, and monteleukast) is being investigated in SCD. Activated leukocytes also produce various proinflammatory cytokines including IL-1β. Canakinumab in a monoclonal antibody that targets IL-1β. Invariant natural killer T cells (iNKTs) exhibit an activated phenotype and amplify the inflammatory response to hypoxia/reperfusion injury in SCD by producing IFN-ϒ. NKTT120 is a humanized monoclonal antibody that specifically depletes iNKTs. Platelets contribute to inflammation. Omega-3 fatty acids, in addition to favorably altering sRBC fatty acid membrane composition, have a myriad of anti-inflammatory effects and target included leukocytes, platelets, and endothelial cells. iTCR, invariant T-cell receptor; PLA2, secretory phospholipase A2. Adapted from Morrone et al48 with permission.